Multifunctionality of PAI-1 in fibrogenesis: evidence from obstructive nephropathy in PAI-1-overexpressing mice.

Matsuo S, López-Guisa JM, Cai X, Okamura DM, Alpers CE, Bumgarner RE, Peters MA, Zhang G, Eddy AA
Kidney Int. 2005 67 (6): 2221-38

PMID: 15882265 · DOI:10.1111/j.1523-1755.2005.00327.x

BACKGROUND - Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of chronic kidney disease based on its up-regulated expression and on the beneficial effects of PAI-1 inhibition or depletion in experimental models. PAI-1 is a multifunctional protein and the mechanisms that account for its profibrotic effects have not been fully elucidated.

METHODS - The present study was designed to investigate PAI-1-dependent fibrogenic pathways by comparing the unilateral ureteral obstruction model (UUO) (days 3, 7, and 14) in PAI-1-overexpressing mice (PAI-1 tg) to wild-type mice, both on a C57BL6 background.

RESULTS - Following UUO, total kidney PAI-1 mRNA and/or protein levels were significantly higher in the PAI-1 tg mice (N= 6 to 8/group) and fibrosis severity was significantly worse (days 3, 7, and 14), measured both as Sirius red-positive interstitial area (e.g., 10 +/- 3.2% vs. 4.5 +/- 1.0%) (day 14) and total kidney collagen (e.g., 11.1 +/- 1.7 vs. 6.2 +/- 1.3 microg/mg) (day 14). By day 14, the expression of two normal tubular proteins, E-cadherin and Ksp-cadherin, were significantly lower in the PAI-1 tg mice (3.2 +/- 0.5% vs. 11.7 +/- 5.9% and 2.6 +/- 1.6) vs. 6.2 +/- 0.8%, respectively), implying more extensive tubular damage. At least four fibrogenic pathways were differentially expressed in the PAI-1 tg mice. First, interstitial macrophage recruitment was more intense (P < 0.05 days 3 and 14). Second, interstitial myofibroblast density was greater (P < 0.05 days 3 and 7) despite similar numbers of proliferating tubulointerstitial cells. Third, transforming growth factor-beta1 (TGF-beta1) and collagen I mRNA were significantly higher. Finally, urokinase activity was significantly lower (P < 0.05 days 7 and 14) despite similar mRNA levels. Gene microarray studies documented that that the deletion of this single profibrotic gene had far-reaching consequences on renal cellular responses to chronic injury.

CONCLUSION - These data provide further evidence that PAI-1 is directly involved in interstitial fibrosis and tubular damage via two primary overlapping mechanisms: early effects on interstitial cell recruitment and late effects associated with decreased urokinase activity.

MeSH Terms (14)

Animals Fibrosis Gene Expression Profiling Genotype Kidney Kidney Tubules Mice Mice, Inbred C57BL Nephritis, Interstitial Plasminogen Activator Inhibitor 1 Procollagen RNA, Messenger Ureteral Obstruction Urokinase-Type Plasminogen Activator

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